YT YouTube2Text

YouTube2Text → Transcripts → Seminario 12 Herencia monogénica autosómica dominante y recesiva - Sebastián Giusti

Seminario 12 Herencia monogénica autosómica dominante y recesiva - Sebastián Giusti — Transcript

by Biología Molecular y Genética FMED - UBA · 5,718 words · 978 segments · language en · Watch on YouTube

Open in transcriber Summarize with AI Download SRT/VTT

Full transcript

0:02Hello, how are you? In today's class,
0:05we are going to analyze classical
0:07inheritance patterns. In particular, we
0:10will analyze autosomal inheritance
0:13patterns related to genetic diseases.
0:20When we speak of monogenic or Mendelian
0:23alterations in the context of medical
0:25genetics, we are talking about those
0:28clinical conditions, sets of signs and
0:31symptoms, that are determined by the
0:34presence in the genome of pathogenic
0:37allelic variants found in a single gene
0:40. And this adjective, Mendelian, is
0:45conferred on this group of entities
0:48because the manifestation patterns of
0:51these entities, and also the
0:54recurrences across generations, follow
0:57some principles originally described by
1:00Mendel, which we will try to interpret
1:04in this context with some elements of
1:07cell and molecular biology and some
1:10specificities that occur in the medical
1:13context. For example, the zero law or
1:18principle of dominance as the first
1:21Mendelian principle alludes to the fact
1:24that signs and symptoms, like the
1:27characteristic trait that we will
1:30analyze in the context of these
1:33entities that belong to the phenotype,
1:36are traits that can be characterized as
1:39dominant or recessive. So, these terms,
1:45dominant and recessive, are terms that
1:48apply to the phenotype, traits
1:52particular to those that manifest in
1:55this particular context. And those
1:59traits will be dominant for which the
2:02presence of a single pathogenic variant
2:06in the genome is enough for it to
2:09manifest. On the other hand, those
2:12characteristics of the phenotype, in
2:15particular the manifestation of signs
2:17and symptoms, will be recessive if the
2:20presence in diploidy of two pathogenic
2:22variants of the same gene is necessary,
2:25one of maternal origin and one of
2:27paternal origin. So, in that context,
2:34given a trait, for example, that is
2:37dominant, the pathogenic variant is
2:41usually represented with an uppercase
2:44letter. Whereas if the entity is
2:49recessive, the pathogenic variants are
2:52noted with lowercase letters to
2:55symbolize them. I would like to clarify
3:01, then, that this trait of dominance
3:04and recessiveness is an aspect of the
3:06phenotype and we should not confuse it
3:09with an aspect of the genotype. For
3:13example, denominations such as healthy
3:16allele or sick allele would be
3:18confusing the level of the healthy or
3:21sick phenotype with the level of the
3:23genotype, with the presence of which
3:26allelic variants of which an individual
3:29is a carrier. It is also true that many
3:33textbooks use somewhat imprecise
3:36terminology when referring to the
3:38dominant allele or the recessive allele
3:41, because there they are also mixing
3:44levels of the genotype and the
3:46phenotype. In the context of our
3:50subject, following this ordering, the
3:54allelic variants will then be
3:56pathogenic or non-pathogenic, normal
4:00variant, or wild type, and on the other
4:03hand, a trait will be dominant or
4:06recessive. The second Mendelian
4:12principle allows us, Before moving on
4:17to the second Mendelian principle, I
4:19would like to recall that this
4:21principle of dominance assumes the
4:23diploid constitution of our genome;
4:25that is, for each of these allelic
4:27variants, we will have one of maternal
4:30origin and one of paternal origin. A
4:35particular feature of pathogenic
4:38variants of dominant traits is the fact
4:40that, usually, when they are present
4:43both maternally and paternally, this
4:46configuration is severe enough to be
4:48lethal. Thus, it is common for those
4:54individuals who manifest signs or
4:57symptoms of a dominant genetic
4:59pathology to have a heterozygous
5:02genetic constitution with the presence
5:05of a single pathogenic variant in their
5:08genome. The second law of Mendel, which
5:15is law one or the principle of
5:19segregation, alludes to the fact that,
5:25when a cross occurs between two
5:28individuals, the allelic variants of
5:30each of those individuals separate,
5:33segregating into different cells, in
5:36the gametes that each of these
5:38individuals produces. And the
5:43particular combination of zygotes that
5:45can be produced from the combination of
5:48the gametes of these two individuals is
5:50represented in this type of scheme
5:52called Punnett squares, named after the
5:55English geneticist who popularized them
5:57. It is important to point out, then,
6:01that what is being represented here are
6:06the probabilities that occur in each
6:08fertilization for the formation of
6:10zygotes of different allelic
6:12constitution. Finally, Mendel's law 2
6:18or the principle of independent
6:22assortment would apply in this context
6:26in the sense that those allelic
6:29variants that belong to other genes are
6:32distributed independently of the
6:34allelic variants that occupy the
6:37pathological condition we are analyzing
6:40here. In particular, for example, the
6:43allelic variants of primary sexual
6:45determination found on sex chromosomes
6:48are distributed independently of these
6:50allelic variants that we are analyzing
6:53in today's class. And that will give a
6:56characteristic to the inheritance
6:59patterns we analyze, which is the fact
7:01that the manifestations of signs and
7:04symptoms are equally likely to be found
7:07in XX or XY individuals. It is
7:11important to note that the recurrence
7:14of affected individuals in different
7:17generations, which is what we call an
7:20inheritance pattern, is usually the
7:22earliest indicator that the pathology
7:25at play is of the Mendelian type.
7:31Usually, in the first consultations
7:34with the doctor, with the geneticist,
7:37information is often gathered in
7:39interviews to build biological
7:42relationships and classify individuals
7:45in a given family as affected or
7:47unaffected. Hm. that is, according to
7:51their phenotype, if they manifest signs
7:54and symptoms or if they do not. And,
7:57based on this distribution of affected
8:00or unaffected individuals, we can
8:02hypothesize about the presence or
8:05absence of an inheritance pattern
8:07compatible with a monogenic entity;
8:10that is, compatible with the existence
8:12of a single pathogenic variant in a
8:15single gene being transmitted from
8:17generation to generation and explaining
8:20this particular recurrence of affected
8:23or unaffected individuals. There are
8:28different inheritance patterns. In
8:30today’s class, we are going to
8:32analyze two of them: autosomal dominant
8:35and autosomal recessive patterns. And
8:38we will leave inheritance patterns
8:40linked to sex chromosomes for a later
8:43class. What is at stake in this
8:47classification is the location of the
8:50gene whose pathogenic variants are
8:53causing the signs and symptoms. In
8:56today’s class, we will focus on
8:59inheritance patterns that result from
9:02the presence of pathogenic variants
9:05located on one of the autosomal pairs,
9:08which are pairs 1 through 22 in human
9:11chromosomes. Instead, in the next class
9:15, you will see the particularities of
9:17the inheritance pattern when a
9:19pathogenic variant is on one of the
9:21members of the sex pair, or pair 23.
9:26Let us begin now by studying the first
9:30of these classical inheritance patterns
9:33, the one characteristic of autosomal
9:36dominant entities. This tree we see
9:43here reflects some of the typical
9:45characteristics of this inheritance
9:47pattern. We can observe, for example,
9:50that we have affected individuals in
9:54multiple generations, and not only that
9:58, but every affected individual has at
10:01least one affected parent, and we see
10:05no obvious differences between affected
10:09male and female individuals. Let us
10:15analyze the characteristics of this
10:17inheritance pattern one by one. Let us
10:19try to reason each one of them. We said
10:27that one of the first characteristics
10:29is that the affected person also has
10:31affected ancestors. Let us think that,
10:34as we said at the beginning, affected
10:37individuals usually have a heterozygous
10:40genetic constitution; that is, they
10:42typically present a single pathogenic
10:45variant from a single parental origin,
10:47because usually the biallelic presence
10:50of pathogenic variants tends to be very
10:53severe and, in general, is not
10:55compatible with life in most entities,
10:58although not in all. So, if we think,
11:02for example, of this individual, an
11:05affected individual XI, we will ask
11:07ourselves, given that they are affected
11:10and possess a pathogenic variant in
11:12their genome, they must have inherited
11:14it from one of their parents. And
11:18therefore, that parent who possesses
11:20that pathogenic variant—since this
11:22trait is dominant and a single
11:24pathogenic variant is sufficient for
11:27signs and symptoms to manifest—then
11:29that parent will also be affected. We
11:32can apply a similar reasoning to all
11:35affected individuals. There is no
11:40skipping of generations. It implies
11:42what we said, that an affected
11:45individual always has at least one
11:47affected parent, and this repeats as we
11:50go up the generations. Another
11:54characteristic feature of this
11:56inheritance pattern is that there is a
11:5850%recurrence risk in the offspring of
12:00affected individuals. To understand
12:05this percentage, we must reason that
12:08affected individuals usually form
12:11reproductive pairs with unaffected
12:14individuals, meaning they carry no
12:17pathogenic variant. So, we can
12:21represent, for example, using this
12:23Punnett square, the possible zygotes
12:25from a cross between an affected
12:27individual, meaning one who possesses a
12:29pathogenic variant in their genome and
12:30the other does not, with an individual
12:32who does not possess any pathogenic
12:34variant. And the result of this Punnett
12:39square is that 50%of the zygotes will
12:41carry the pathogenic variant and
12:44therefore manifest the signs and
12:46symptoms, which is where the 50%
12:48recurrence risk for offspring arises.
12:53Again, applying Mendel's second law,
12:56the principle of independent assortment
12:59, we can think that for pair 23, for
13:02example, if we consider this male
13:05individual is the carrier of the
13:07pathogenic variant, uh, in conjunction
13:12with this pathogenic variant, some
13:15gametes will carry this individual's Y
13:18chromosome and others will carry this
13:21individual's X chromosome from pair 23;
13:25and therefore, there will be an equal
13:28distribution between XX and XY
13:30offspring that carries the signs and
13:34symptoms. Let's analyze an autosomal
13:40dominant entity characteristic of
13:43medical genetics, such as
13:45achondroplasia, which is a bone
13:47disorder present in approximately one
13:51in every 25,000 births. The
13:56characteristic signs and symptoms of
13:59achondroplasia are short stature and
14:02the presence of rhizomelic shortening
14:05of the limbs, meaning the shortening of
14:08the proximal part of the limbs in
14:10particular. There are also differences
14:15in the proportions between the head and
14:18body compared to unaffected individuals
14:21and facial features pathognomonic to
14:24achondroplasia. These individuals
14:28usually present with lumbar lordosis,
14:31and one of the most common
14:33complications of this bone disorder is
14:36the presence of lumbosacral spinal
14:38stenosis, which compresses the spinal
14:41cord nerve roots and is a frequent
14:43complication in this context. What is
14:49the physiological process that is
14:52affected in the context of
14:54achondroplasia? It has been determined
14:58through research in the fields of
15:01physiology that it is the process of
15:04long bone growth that is specifically
15:07affected in this condition. In
15:11particular, this process is
15:13endochondral ossification. You surely
15:16know that long bones grow primarily
15:19through the extension of cartilaginous
15:23tissue. Hmm. And this cartilage model
15:27is what will later mineralize its
15:30extracellular matrix to become bone. In
15:36particular, long bones have, uh, in the
15:38bone epiphysis, a section called the
15:41growth plate, where chondrocytes—the
15:44characteristic cartilage cells—are in
15:47active proliferation in individuals who
15:50are still growing. What happens in
15:55individuals with achondroplasia? The
15:59molecular mechanism was determined more
16:03precisely about 30 years ago, in 1994,
16:06when a research group published a paper
16:10in the journal*Cell*, a very
16:12prestigious journal in the biomedical
16:15context, where they were able to
16:20determine the gene whose pathogenic
16:23variants caused the signs and symptoms
16:26of achondroplasia. Note then that prior
16:31to 1994, it was already known that
16:34achondroplasia was a monogenic entity
16:37just by its inheritance pattern, but
16:40until that moment, it was not known
16:43which gene or encoded protein had
16:46pathogenic variants that determined the
16:50appearance of the signs and symptoms.
16:54And in this work, they identified that
16:57the gene involved is a mitogen receptor
17:00. It is the fibroblast growth factor
17:04receptor 3. This receptor is a tyrosine
17:08kinase type receptor, very common as a
17:11mitogen receptor, which, when it binds
17:13to its ligand, dimerizes and begins an
17:16intracellular signaling cascade that
17:19leads to promoting the proliferation of
17:21the cells that have received this
17:24signal. It has been determined that
17:29individuals with achondroplasia in
17:31practically all cases have a mutation
17:34called G380R. This is a point
17:40substitution mutation in the genome
17:44that causes one codon to be replaced by
17:48another that encodes a different amino
17:51acid. In particular, this generates a
17:55protein where, at position 380 of the
17:58polypeptide, where the standard or
18:01wild-type variant has a glycine amino
18:04acid, the pathogenic variant has an
18:07arginine amino acid. And this,
18:11precisely because it is a mutation that
18:14changes one codon for another and,
18:16therefore, one amino acid for another,
18:18we call it a missense mutation. Now, it
18:22was surprising to find that the effect
18:26this mutation—this variant—had on
18:29protein function was a gain of function
18:32. That is, receptors with these
18:35pathogenic variants do not function
18:38less; on the contrary, they function
18:41with much higher activity than the
18:44levels......wild-type, the normal
18:48levels. But one of the consequences of
18:51this overactivation caused by this
18:53pathogenic variant is that the
18:55overactivation of this mitogen receptor
18:58induces......uh, the triggering of cell
19:03death by apoptosis of the chondrocytes,
19:06yes? which are cells expressing this
19:10receptor, and therefore, the death of
19:13chondrocytes in the epiphysis of long
19:16bones leads to an early termination of
19:20the bone elongation process, which
19:23causes much of the symptomatology of
19:26achondroplasia. In this case, then, if
19:31we think about the possible effect of
19:34these pathogenic variants, of these
19:36mutations on gene function, in this
19:39case we are talking about a gain of
19:42function where an allelic variant
19:44became hyper-functional, a hypermorphic
19:47allele. And usually when the effect a
19:54mutation has on the function of a gene
19:58product is a gain of function, this
20:01usually corresponds to dominant traits.
20:05Hm. That is to say, the presence of a
20:08single hyper-functional allelic variant
20:11is usually sufficient for the
20:13manifestation of the signs and symptoms
20:15. Hm. The same also occurs in the case
20:19where a very particular loss of
20:21function occurs called antagonism,
20:23where there is a loss of function that
20:26opposes the normal function of the
20:28allele. Let's look at some potential
20:35complications in the interpretation of
20:38pedigrees or family trees in the
20:41context of achondroplasia. Let's look
20:45at this particular pedigree. In many
20:48cases, it happens that in
20:50achondroplasia, an affected individual
20:53appears in a family, but when one
20:55analyzes the family history, one finds
20:58none. And this occurs relatively
21:02frequently in the case of
21:03achondroplasia, where 80%of cases are
21:06caused by de novo mutations. That is,
21:10when an individual affected by a
21:13dominant condition appears with a total
21:17absence of family history, a hypothesis
21:21we can make and which is usually
21:23corroborated is that there was a fresh
21:27mutation. Hm. For example, it could
21:31have happened that one of the parents
21:33had a pathogenic variant restricted
21:36only to their germ line that was
21:38transmitted to their offspring. Hm. And
21:43something consistent with this
21:45hypothesis, it is given, it has been
21:48proven, for example, that many of these
21:51mutations come from the paternal parent
21:54. Hm. And this predominance of the
22:01paternal origin, in the case of de novo
22:04mutations, which occur in the case of
22:08achondroplasia and also many other
22:11monogenic dominant entities, is due to
22:14the differences in female and male
22:17gametogenesis. Let's remember from
22:21previous seminars that when cells
22:23divide, some mutations usually become
22:26fixed, corresponding to those
22:28pre-mutational damages that could not
22:31be repaired by the DNA repair
22:34mechanisms. So, the higher the number
22:40of cell replication cycles, the higher
22:43the rate of mutation accumulation; that
22:46is, the total number of mutations that
22:49accumulate in a cell lineage that has
22:52undergone more replication cycles will
22:55be greater than in another cell lineage
22:58that has had fewer replications. In
23:03this context, if we consider that male
23:06gametogenesis is characterized by
23:09constant mitosis throughout an
23:12individual's fertile life, as opposed
23:15to female gametogenesis, where oocytes
23:19are arrested in meiosis 1 from fetal
23:22life, we will see a very large
23:25difference in the number of replication
23:28cycles, and this causes the risk of new
23:33mutations appearing to increase as
23:36paternal age—and therefore the number
23:40of mitotic replication cycles of germ
23:43cell progenitors—increases. What we
23:49have just analyzed, the existence of de
23:52novo mutations, allows us to add some
23:54exceptions to the characteristics of
23:57the autosomal dominant inheritance
23:59pattern we saw recently. For example,
24:02when we said that the affected
24:05individual also has affected ancestors,
24:07while that is true, there is an
24:10exception in the case of de novo
24:12mutations; in those cases, we will not
24:15have affected parents. Let's analyze
24:19another exception which is the
24:23existence of generational skips. What
24:28do we mean by a generational skip? For
24:33example, if we analyze this pedigree,
24:36we see that we have affected
24:38individuals who do not have a parent
24:40affected by that particular entity, but
24:43at the same time, that unaffected
24:46parent has a parent from the previous
24:49generation who is affected. That is to
24:53say, how can it be possible for this
24:58individual, who possesses a pathogenic
25:00variant in their genome, to have
25:03skipped a generation to affect the
25:05individuals of the third generation? To
25:10clarify this apparent paradox, what
25:13happens is that the generational skip
25:16is the manifestation of signs and
25:19symptoms; it is the phenotypic aspect,
25:22but the pathogenic variant is present
25:25in this individual and then was
25:27transmitted to the offspring. So, this
25:33means that there are some cases where
25:35an individual may have a pathogenic
25:38variant of a dominant trait in their
25:40genome, but not manifest it at the
25:43phenotypic level. And this attenuation
25:47of what we were saying previously can
25:50be referred to under the concept of
25:53penetrance. Penetrance is the
25:57probability that a person who has the
26:00genotype expected to manifest signs and
26:02symptoms will actually manifest them.
26:06Some entities are 100%penetrant. This
26:10means that 100%of the individuals who
26:12carry a pathogenic variant for that
26:14entity will manifest the signs and
26:17symptoms. Achondroplasia is an example
26:21of a, uh, 100%penetrant entity, but
26:24there are others that are not, having
26:27incomplete penetrance, where not all
26:30individuals carrying the pathogenic
26:33variant show signs and symptoms, but
26:36rather express them in different
26:39proportions, for example, 80%or 60%.
26:44Examples of these dominant entities
26:46with incomplete penetrance are, for
26:48instance, hereditary retinoblastoma or
26:50familial combined hyperlipidemia. What
26:54are the reasons for this reduced
26:56penetrance? Generally speaking, we
27:00could think that environmental factors
27:03or other genes in the genome could be
27:06moderating or attenuating, in certain
27:09individuals, depending on those
27:12environmental characteristics or other
27:15genes in their genome, the
27:17manifestation of signs and symptoms;
27:20but this is general and must be studied
27:23in each specific case, and we do not
27:26yet know the molecular mechanisms of
27:29this incomplete penetrance in all cases
27:32. So, returning to the exceptions or
27:37complications that can arise when
27:40analyzing an autosomal dominant
27:42inheritance pattern, we had mentioned
27:45that de novo mutations were an
27:48exception to the regularity where we
27:51typically see that affected individuals
27:54have at least one affected parent; and
27:58incomplete penetrance helps explain the
28:01exceptions regarding the non-existence
28:04of skipped generations. In other words,
28:08when we see a skipped generation in the
28:11context of a dominant entity, we can
28:14assume it is a case of incomplete
28:17penetrance. Let's now analyze the
28:23second of the inheritance patterns we
28:27are going to refer to in today's class.
28:31Those of autosomal recessive entities.
28:37Let's consider then that if an entity
28:42is recessive, it implies that
28:44individuals who manifest the signs and
28:47symptoms of this entity do so because
28:49they have two pathogenic variants, one
28:52maternal and one paternal, in the same
28:55gene, which are responsible for the
28:57appearance of these signs and symptoms.
29:01Taking this peculiarity into account,
29:05one usually observes that affected
29:11individuals, if there is more than one
29:14in a given family, are usually
29:16biological siblings, where each one of
29:19them has inherited a pathogenic variant
29:22from each of the two parents. It is
29:29also frequent that we find the
29:32appearance of cases of autosomal
29:36recessive entities in cases of
29:40consanguinity. For example, in this
29:44case, there are two consanguineous
29:47individuals, two cousins who have
29:49formed a reproductive couple, and whose
29:52offspring manifest signs and symptoms
29:55of autosomal recessive entities. To
29:59understand these peculiarities, an
30:02aspect we must consider is that these
30:05pathogenic variants are usually
30:08relatively rare in the population. Hmm.
30:12In other words, it is rare for two
30:14individuals who are not biologically
30:17related to share these pathogenic
30:19variants, and therefore, consanguinity
30:22increases the likelihood that very rare
30:25variants in the population, which are
30:27present in individuals sharing part of
30:30their genome because they come from the
30:33same family, if they form a
30:35reproductive couple, will increase the
30:38chance that their offspring will be
30:40homozygous. for these rare variants
30:44within the population. Let's analyze,
30:48taking these characteristics into
30:51account, some regularities present in
30:54this inheritance pattern. As we said,
30:57if there are several affected
30:58individuals, they are usually siblings
31:00of the proband, because precisely what
31:03is difficult is for a reproductive
31:04couple to form that carries pathogenic
31:07variants of the same gene. Hm. So, when
31:10this happens, which occurs with low
31:12probability in general, unless that
31:15couple is consanguineous, where the
31:17probability increases because the
31:20chance of these rare population
31:22variants meeting will increase. When
31:25this happens, then the offspring of
31:28that couple have a high probability of
31:32having this condition. And usually,
31:36this probability, this recurrence risk,
31:38is 25%. Let us consider then that these
31:43unaffected parents are carriers, each
31:46of them, of a pathogenic variant
31:48represented here with a lowercase
31:50letter because we are dealing with a
31:52recessive entity. And if we make a
31:55Punnett square, we will see that 25%of
31:58the possible zygotes in each of the
32:01fertilizations of this couple will
32:04inherit the pathogenic variant from the
32:07mother and the father and therefore
32:10will manifest the signs and symptoms of
32:13the entity. This brings us back to the
32:17concept of thinking about the existence
32:22of obligate carriers. of these
32:24pathogenic variants, we are referring
32:27to those individuals who we can presume
32:30possess the pathogenic variant in their
32:33genome due to their biological
32:35relationship with the affected
32:38individuals. For example, these two
32:42individuals are affected, so we can
32:44assume that both parents are carriers
32:47of a pathogenic variant. And we signal
32:51this with a black dot in the middle of
32:53the symbols that represent them. Also,
32:56all offspring of an affected individual
32:59will be an obligate carrier of that
33:01pathogenic variant. Let's think of the
33:04Punnett square, where an affected
33:06individual with two pathogenic variants
33:08forms a reproductive couple with an
33:10unaffected individual. Hm. We assume
33:15that this individual has no pathogenic
33:17variant precisely because they are very
33:19rare in the population, and it would be
33:22very unlikely that, if this cross is
33:24not consanguineous, the exogamous
33:26individual who does not come from that
33:28family would have a pathogenic variant
33:30of the same gene. and all will carry a
33:40pathogenic variant, in this case, a
33:42lowercase one. and therefore they are
33:44also obligate carriers. I would like to
33:48clarify that there could be other
33:50carriers of the pathogenic variants in
33:53this family, but we cannot predict who
33:55they are, or if they are carriers,
33:58based solely on their biological
34:00relationships, and we would need to use
34:02molecular diagnostic techniques to
34:05confirm it. We don't call those other
34:07carriers "obligate"; obligate carriers
34:10are those we can infer simply through
34:13their biological relationships. Another
34:20regularity present in this inheritance
34:23pattern is that men and women can be
34:26equally affected, because if this
34:29pathogenic variant is found on an
34:32autosomal pair from 1 to 22, it will be
34:36distributed independently of the sex
34:39chromosomes and will therefore affect
34:43them equally. Hm. Both men and women.
34:49And as we just mentioned, there is an
34:51increased risk in consanguineous
34:54couples who may put into homozygosity
34:56variants that are otherwise rare in the
34:59population. Summarizing then, there are
35:04some specific risk factors for these
35:06autosomal recessive diseases; for
35:09example, consanguinity, but also
35:11geographical, cultural, or religious
35:14isolation. Following the same line of
35:18thought, when there are very closed or
35:21very small communities that tend to
35:24form reproductive pairs among
35:26themselves, it is not uncommon that,
35:29within a few generations, individuals
35:31who form a reproductive pair. If we
35:35analyze their ancestors, we find some
35:37connections, meaning we find a certain
35:40degree of endogamy, and this increases
35:42the probability that pathogenic
35:45variants that are very specific to that
35:47group of individuals, but rare in the
35:50general population, become homozygous.
35:55Although it can also happen in very
35:57limited cases that there is some
36:00pathogenic variant, some mutation, that
36:02is prevalent in a particular population
36:05. And this happens in the Argentine
36:08population, for example, with an entity
36:11that is cystic fibrosis, which is the
36:13monogenic disease that causes the
36:15highest number of deaths in people of
36:18Caucasian origin. The carrier rate in
36:22Argentina is very high, extremely high
36:25compared to other pathogenic variants
36:28of other recessive entities. It is one
36:32in 30, and therefore the incidence is
36:35quite high, one in every 2,000 births.
36:41Let's look at some peculiarities of
36:43this entity. It was originally
36:46described in the year 1938, when it was
36:49able to be differentiated from celiac
36:52syndrome. And the autopsies of these
36:57children, which were originally found
37:00in children, revealed that unlike
37:02celiac syndrome, the individuals who
37:05had this cystic fibrosis had mucus
37:08plugging in various glandular ducts and
37:11it affected multiple organs, the
37:14respiratory tract, the liver, the
37:17pancreas, the intestine, and the
37:19reproductive tract. These children were
37:24characterized by having low weight and
37:26fat in their stool. They also had
37:29respiratory difficulties such as a
37:31productive cough and pneumonia. And one
37:34of its characteristics that later
37:37allowed for early clinical diagnosis is
37:40that they have very high concentrations
37:43of sodium chloride in their sweat, and
37:46today the sweat test developed by
37:49pediatrician Paul di Sant'Agnese in
37:521953 is used. And when there is a
37:57suspicion of the presence of this
38:01condition, one of the first clinical
38:03tests performed is to measure the
38:05concentration of sodium chloride in the
38:07sweat. It was not until the year 1989
38:15that the gene responsible for cystic
38:18fibrosis was determined. Uh, this gene
38:22was named CFTR, for the acronym in
38:26English for cystic fibrosis
38:28transmembrane conductance regulator;
38:31that is to say, the gene was named
38:35after the pathological entity of its
38:38pathogenic variants. And it could be
38:43seen that the wild-type, unaffected—
38:46that is, non-pathogenic—variant of
38:48that gene encodes a chloride channel
38:51that is expressed in multiple
38:53epithelial cells, including sweat
38:56glands, the lining of the airways, the
38:58intestine, pancreatic ducts, etc. And
39:01this chloride channel allows, for
39:04example, the ionic passage for the
39:08subsequent diffusion of water molecules
39:11, which allows, uh, the liquefaction of
39:16mucous secretions in many ducts. More
39:23than 1,000 pathogenic variants of this
39:25gene have been found in different
39:27individuals affected by cystic fibrosis
39:30. Hmm. That is to say, there are
39:33multiple mutations that can be
39:35pathogenic variants, although some are
39:38much more frequent than others. For
39:41example, particularly in our country,
39:44one of the pathogenic variants, by far
39:46the most frequent, is called
39:48phenylalanine 508. It is a deletion of
39:55three nucleotides in the CFTR gene,
39:58which affects an exon, a coding region,
40:02and results in the deletion of a codon
40:06from the polypeptide chain, where the
40:09amino acid phenylalanine at position
40:13508 is deleted. But this loss of a
40:18single amino acid has enormous
40:20consequences for the protein, as it
40:22misfolds and is degraded prematurely.
40:26In such a way that those individuals
40:29who possess two pathogenic variants of
40:32this nature, of this particular
40:35mutation, have 0%activity of the
40:38chloride channel in their epithelial
40:41cells. Based on this diversity of
40:47mutations and the different effects
40:50these mutations have on protein
40:52activity, these mutations have been
40:55classified into six classes. And this
40:59is generally common, not only for
41:01mutations affecting cystic fibrosis,
41:03but for many other, uh, variants that
41:09have a loss of function as a
41:11consequence of the pathogenic variant.
41:14Hmm. For example, here, classes 1, 2,
41:19and 3 are characterized by having
41:21practically no activity of this protein
41:24product. Uh, On the other hand, the
41:31last classes, which are slightly less
41:34frequent, are mutations where the
41:36function is diminished, but not
41:38annulled. So, from the point of view of
41:45the effect these pathogenic variants
41:48have on the activity of the final gene
41:51product, we can classify these CFTR
41:54gene pathogenic variants into two
41:57classes among those characterized by
42:00loss of function. For example, those
42:04mutations that caused an absence of
42:07protein product because it was
42:08misfolded and degraded, or because it
42:11is not expressed, or because they
42:13generate a totally non-functional
42:15channel. We say they have generated
42:18null alleles, or alleles with an
42:21absence of protein function. Meanwhile,
42:24those pathogenic variants characterized
42:27by less frequent mutations, those that
42:30decrease chloride channel activity
42:32without completely annulling it, we
42:34will call hypofunctioning alleles. And
42:39it is common to observe that those
42:42pathogenic variants characterized by
42:44loss of function, such as null alleles
42:47or hypofunctioning alleles, usually
42:49have recessive inheritance patterns.
42:53And the mechanism that explains this is
42:56haploinsufficiency, that is, the fact
42:59that a single active variant in the
43:02genome is enough to sustain
43:04physiological function so that signs
43:07and symptoms do not appear. It is
43:10necessary, therefore, that both allelic
43:13variants in the genome, the maternal
43:16and paternal, have a loss of function
43:19for the signs and symptoms of the
43:22condition to manifest. That is to say,
43:25the trait is recessive. I would like to
43:33comment, in the context of cystic
43:35fibrosis, on a concept that can be
43:38generalized to many other genetic
43:40entities: the concept of variable
43:42expressivity, which refers to the
43:45different degrees of severity in which
43:47the phenotype can manifest, where we
43:50observe that some individuals are
43:52severely affected and others have
43:54milder phenotypes. What are some of the
44:00mechanisms that explain this variable
44:03expressivity in the context of
44:06monogenic diseases? One of them is
44:09allelic heterogeneity. Again, although
44:14we have mentioned this concept without
44:17referring to it by its proper name, we
44:20know as allelic heterogeneity the
44:23presence of multiple, distinct allelic
44:25variants that can have pathogenicity,
44:28that is, different nucleotide
44:30alterations that will then have an
44:33impact on protein structure and
44:35function. but are different from one
44:38another. For example, the most frequent
44:42mutation, phenylalanine 508, was a
44:45class two mutation, and we can have an
44:48individual who is homozygous for this
44:50class two mutation. And we can have
44:54another individual who is homozygous
44:56for class four mutations, which were
44:59those mutations that decreased but did
45:01not annul the protein function of delta
45:04F508. And we can also have compound
45:08heterozygotes, that is, individuals who
45:11have pathogenic variants of the CFTR
45:13gene, but the variants are different
45:16from each other. So, all these
45:19combinations of different allelic
45:22variants, allelic heterogeneity, could
45:25explain the variability in the severity
45:29of the signs and symptoms that these
45:32individuals have, but it is not the
45:35only source of variability, since even
45:38biological siblings who share the same
45:42combination of allelic variants can
45:45also have expressive. variability. And
45:49that other source of variability is due
45:53to other factors, for example, the
45:56presence of other genes in the genome
46:00that affect protein function. It is
46:06important, therefore, to determine
46:09which particular allelic variants are
46:12explaining the appearance of signs and
46:15symptoms, because in some cases there
46:18are therapeutic interventions that are
46:21specific to a particular pathogenic
46:24variant. An example of this is a drug
46:29named to treat cystic fibrosis called
46:33Ivacaftor, which is a pharmacological
46:36potentiator of chloride channel
46:39activity; but, in particular, it is
46:42specific to pathogenic variants found
46:46in class three, as it allows for the
46:49activation of channels already present
46:52in the membrane. That is, the
46:57application of this treatment would be
46:59useless, it would have no effect on
47:01individuals affected with mutations of
47:03the first two classes, where there is
47:05no receptor on the membrane that is
47:07expressed due to the characteristics of
47:09that pathogenic variant. Hm. So, this
47:14helps us think that the molecular
47:16description of pathogenic variants has
47:19an effect on the treatments that can be
47:22offered to certain patients in the
47:25clinic. This is a step towards the
47:29personalization of medical treatment in
47:32the context of genetic diseases. I was
47:40telling you then that the second of the
47:45factors that explains variable
47:47expressivity is modifier genes, which
47:49is the presence of other genes in the
47:51genome that can change the degree of
47:56severity with which the phenotype
47:58manifests. Let's look at an example. It
48:01has been studied that variations in
48:04expressivity in individuals who have
48:07the same class of pathogenic variant
48:09mutations for the CFTR gene could be
48:12explained by the presence of other
48:15differential allelic variants in genes,
48:18for example, that regulate the
48:20inflammatory response, since, for
48:22example, individuals with cystic
48:26fibrosis tend to have frequent
48:28pulmonary infections. And those who
48:33have allelic variants of genes that
48:36induce an aggressive inflammatory
48:39response tend to have a worse prognosis
48:42and more severe symptoms than those who
48:46have allelic variants that are less
48:49potent in inducing an inflammatory
48:53response. Finally, environmental
49:00factors could also affect the degree of
49:03severity with which the phenotype
49:06manifests. For example, if we consider
49:10an individual with more precarious
49:12socioeconomic conditions, where health
49:16and nutritional factors are deficient,
49:19that individual will likely have a
49:22greater severity in the manifestation
49:25of their phenotype compared to someone
49:28who has had access to material
49:32conditions to support their nutrition
49:35and health. To conclude this class, I
49:42would like to propose an exercise,
49:45since while the focus of the course is
49:48not for you to memorize clinical charts
49:51with their signs and symptoms, it is
49:54for you to be able to use concepts of
49:57Mendelian genetics in particular to
49:59interpret different medically important
50:03entities. I suggest you look up various
50:07autosomal entities in the bibliography,
50:10such as phenylketonuria, congenital
50:12adrenal hyperplasia, or
50:14neurofibromatosis type 1, to take three
50:16examples, and try to determine for each
50:19of these entities: what is the
50:21inheritance pattern, what is the
50:23affected gene, whether there are
50:25frequent mutations or not, how the
50:31molecular mechanisms work, if they are
50:33known, and how they relate to the
50:35degree of phenotypic involvement,
50:38whether they are entities with complete
50:40or incomplete penetrance, what the
50:42variability of their expressivity is
50:44like, and whether there is a treatment
50:47available or not. Again, I believe this
50:51type of exercise will allow you to use
50:55the concepts, apply the concepts in a
50:58way that is a way of knowing whether
51:03you have understood them deeply or not.
51:07With this, we finish today's class and
51:09I will see you in our next meeting.

About this transcript

This page contains the full transcript of Seminario 12 Herencia monogénica autosómica dominante y recesiva - Sebastián Giusti by Biología Molecular y Genética FMED - UBA, generated from the public captions YouTube serves with the video. The transcript has 5,718 words across 978 segments, with the original timestamps preserved so you can click any line to jump to that moment in the embedded player.

What you can do with it

Use the transcript to take notes, quote the speaker, build a study guide, generate a summary with ChatGPT or Claude via the YouTube Summary tool, or export it as a timed subtitle file with YouTube to SRT. You can also re-open it in the transcriber to translate the transcript into 100+ languages.

Free YouTube transcript tool

YouTube2Text is a free YouTube transcript generator — no signup, no daily limit. Paste any YouTube link and get the full transcript instantly, with timestamps, click-to-jump, translation to 100+ languages, AI prompts for ChatGPT, Claude, and Gemini, and exports to TXT, SRT, VTT, or Markdown.